The present invention relates to new aromatic amides, their preparation process and their use as medicaments.
A subject of the invention is the compounds of formula (I): 
in which:
Y represents an oxygen atom, or an N-Nalk1 or NOalk2 radical in which alk1 and alk2 represent an alkyl radical, containing up to to 12 carbon atoms optionally interrupted by one or more oxygen, sulphur or nitrogen atoms, optionally substituted by one or more halogen atoms, by an aryl radical optionally substituted by one or more halogen atoms, by a heterocyclic radical, by one or more 
radicals in which Ra and Rb identical or different from one another represent a hydrogen atom, an optionally substituted alkyl radical containing up to 8 carbon atoms, or Ra and Rb form together with the nitrogen atom to which they are joined to heterocycle which can contain in addition another heteroatom chosen from oxygen, sulphur or nitrogen, X represents a hydrogen atom, a hydroxyl radical, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical optionally interrupted by one or more oxygen, sulphur and or nitrogen atoms, containing up to 12 carbon atoms, optionally substituted by one or more halogen atoms, by a heterocyclic radical, one or more free or esterified OH, Cxe2x89xa1N, NO2, 
radicals in which Ra and Rb, identical or different, represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, or Ra and Rb form together with the nitrogen atom to which they are linked a heterocycle optionally containing another heteroatom chosen from nitrogen, sulphur or oxygen, or X represents an alkoxy radical or a 
radical in which Re represents an alkyl radical containing up to 8 carbon atoms, optionally substituted by one or more of the substituents indicated above, or X represents an NRcRd radical in which Rc and Rd identical or different, represent a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, optionally substituted by one or more of the substituents indicated above, or Rc and Rd form together with the nitrogen atom to which they are linked a heterocycle optionally containing another heteroatom chosen from nitrogen, sulphur or oxygen,
Z represents a hydrogen or halogen atom or a free, etherified or esterified OH radical,
R2 represents a hydrogen or halogen atom,
R3 represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or a halogen atom,
R represents a hydrogen atom or an alkyl radical containing up to 4 carbon atoms,
R1 represents a hydrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 8 carbon atoms, optionally substituted by one or more halogen atoms, a Cxe2x89xa1N radical, an aryl radical containing up to 14 carbon atoms,
R5 represents a hydrogen atom, an O-alkyl radical containing up to 4 carbon atoms,
either R6 represents an alkyl or CH2 xe2x80x94Oxe2x80x94alkyl radical, in which alkyl represents an alkyl radical containing up to 8 carbon atoms,
R7 represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms,
or R6 and R7 form together with the carbon atom which they carry a ring containing up to 8 carbon atoms, as well as the salts of the compound of formula (I), when the compounds of formula (I) have a basic function.
As examples of salts there can also be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, paratoluenesulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric and especially stearic, ethylsuccinic or laurylsulphonic acids.
In the definition of the substituents:
the alkyl, alkeny or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl radical,
the halogen is preferably fluorine or chlorine, or bromine,
the aryl radical is preferably the phenyl radical,
the heterocyclic radical is preferably the pyrrolyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl, thiazolyl, azetidinyl, aziridinyl radical.
A more particular subject of the invention is the compounds of formula (I) in which Y represents an oxygen atom, those in which Y represents an NO-alkyl radical in which the alky radical contains up to 4 carbon atoms, for example those in which Y represents the NOC2H5 radical.
Among the preferred compounds of the invention there can be mentioned the compounds of formula (I) in which X represents an alkyl radical containing up to 4 carbon atoms and in particular the CH3 radical, or also those in which X represents an NH2 radical, or also those in which X represents the: 
radical.
Among the preferred compounds of the invention, there can be mentioned the compounds of formula (I) in which R1 represents a 
radical
those in which R represents a hydrogen atom, or also those in which R3 represents a methyl radical, or also those in which Z represents a hydrogen atom, or also those in which R2 represents a hydrogen atom, or also those in which R5 represents an OCH3 radical, or also those in which R6 represents a methyl radical, or also those in which R7 represents a methyl radical, those in which R7 represents an ethyl radical, those in which R6 and R7 form with the carbon which carries them a cyclopentyl radical.
Among the preferred compounds of the invention, there can be mentioned the compounds whose preparation is given hereafter in the experimental part and quite particularly the compounds of 1, 2, 3, 4, 5 and 9.
The products of general formula (I) have a very good antibiotic activity on gram ⊕bacteria such as staphylococci, streptococci, pneumococci, enterococci, listeria, anaerobes.
The compounds of the invention can therefore be used as medicaments in the treatment of germ-sensitive infections and in particular, in that of staphylococcia such as staphylococcal septicaemias, malignant staphylococcia of the face or skin, pyodermitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as primitive or post-influenzal acute angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute agina, otitis, sinusitis, scarlatina, pneumococcia such as pneumonia, bronchitis and diphtheria. The products of the present invention are also active against infections caused by germs such as Haemophilus influenzae.
Therefore a subject of the invention is the compounds of formula (I) as medicaments.
A more particular subject of the invention is, as medicaments, the compounds indicated above as preferred compounds.
A subject of the invention is also the pharmaceutical compositions containing at least one of the medicaments defined above as active ingredient.
These compositions can be administered by buccal, rectal, parenteral route, or by local route as a topical application on the skin and mucous membranes, but the preferred administration route is the buccal or injectable route.
They can be solids or liquids and be presented in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with the excipients usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
These compositions can also be presented in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example, apyrogenic sterile water.
The does administered is variable according to the affection treated, the patient in question, the administration route and the product considered. It can be, for example, comprised between 50 mg and 3000 mg per day by oral or injectable route for an adult for the preferred products.
A subject of the invention is also a process for the preparation of the compounds of formula (I), characterized in that a compound of formula (II): 
in which the radicals R2, R3, Z, R5, R6 and R7 retain their previous meaning, OW represents a blocked hydroxyl group and Wxe2x80x2 represents an alkyl or Oalkyl radical containing up to 4 carbon atoms, is subjected
to the action of an agent capable of introducing the 
radical
or of a series of operations capable of introducing the 
radical
R and R1 retaining their previous meaning,
to the action of an agent capable of releasing the hydroxyl radical from the OW radical,
to the optional action of an agent capable of replacing Wxe2x80x2 by the X radical which is different from alkyl or Oalkyl,
to the optional action of an agent capable of introducing the Y radical which is different from oxygen,
to the optional action of a salification agent.
The products of formula (II) used at the start of the process of the invention are new products, the preparation of certain products of formula (II) is given hereinafter in the experimental part.
The other products of formula (II) can be synthesized by analogy with the processes described in the experimental part.
A more particular subject of the invention is the compounds of formula (II) the preparation of which is given in the experimental part.
In a preferred embodiment:
The introduction of the 
radical is carried out in several stages, firstly the action of a substituted or unsubstituted phenylchloroformate, then the action of a compound of formula R1ONHR in which R1 and R retain their previous meaning
the OH group is blocked in the form of a tetrahydropyrane,
the release of the hydrolysis by acid hydrolysis, for example by the action of paratoluenesulphonic acid,
the optional conversion of the Wxe2x80x2 radical to the X radical and the conversion of the Y radical is carried out according to the standard processes. For the Y radical, it is in particular the action of an amine.
A subject of the invention is also a process characterized in that the product of formula (II) is prepared by the action of a compound of formula (III) 
in which R5, R6 and R7 retain their previous meaning on a compound of formula (IV) 
in which R2, R3 and Z retain their previous meaning, then of a blocking agent of the free hydroxyl radical. The following compounds of formula (III) are new and are in themselves a subject of the present invention, namely: 
The following examples illustrate the invention without however limiting it.
A solution containing 80 g of ethyl 7-hydroxy-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyrane-3-carboxylate in 1200 ml of methylene chloride is agitated under an argon atmosphere. 52.07 g of 6-deoxy-5-C-methyl-4-O-methyl-L-lyxo-hexopyranose and 71.22 g of triphenyl-phosphine are added at 0xc2x0 C.
54.78 ml of diisopropyl azocarboxylate is introduced at 0xc2x0 C. After one hour of reaction at ambient temperature, 34 g of triphenylphosphine and 25.6 ml of diisopropyl azocarboxylate are added again. Agitation is carried out for 16 hours at ambient temperature followed by evaporation to one-half volume and filtering the suspension eluting with the toluene/isopropyl alcohol mixture (95-5). When the product starts to pass through, a mixture with 6% isopropyl alcohol is carried out. After saponification in 700 ml of hexane/ethyl acetate mixture (4-5), 64.4 g of sought product is obtained that is used as it is in the following stage.
50 g of a solution from stage A in 500 ml of methylene chloride is agitated under argon at ambient temperature. 42 ml of diisopropylethylamine and 9.66 g of imidazole are added. The solution is agitated for 15 minutes or cooled down to 0xc2x0 C., 20.64 ml of triethylchlorosilane is added dropwise over 30 minutes, and agitation is carried out for 2 hours at 0xc2x0 C. The reaction medium is poured into a molar solution of sodium dihydrogen phosphate. Extraction is carried out with methylene chloride followed by drying and evaporating to dryness. 66.27 g of product is recovered that is purified on silica eluting with a methylene chloride mixture at 0.75% of acetone. When the product is nearly isolated, eluting is carried out with a methylene chloride solution at 1% of acetone. 41.04 g of sought product is obtained after saponification in a hexane/ethyl acetate mixture (9-1). NMR 1H (300 MHz, CDC13, ppm)
0.73 (q, 6H), 1.04 (t, 9H), 1.04 (s, 3H), 1.30 (s, 3H), 1.40 (t, 3H), 2.24 (s, 3H), 2.74 (d, J=1 Hz, mobile 1H), 3.28 (d, 1H, J=9), 3.53 (s, 3H), 4.05 (M, 1H), 4.27 (dd, 1H, J=3.5 and 9 Hz), 4.43 (q, 2H), 5.31 (s, 2H), 5.62 (d, 1H, J=2 Hz), 7.12 (d, 1H, J=9 Hz), 7.43 (m, 5H), 7.63 (d, 1H, J=9 Hz).
A solution containing 40.9 g of product of the previous stage in 400 ml of methylene chloride is agitated under argon at ambient temperature. A few drops of paratoluene sulphonic acid, then 11.54 ml of dihydropyrane are added. Agitation is carried out for 2 hours at ambient temperature. 6 g of bisodium carbonate is added. The suspension is agitated for 15 minutes followed by diluting with 1000 ml of a hexane/ethyl acetate mixture (2-1) and pouring onto water. The reaction mixture is decanted, the organic phase is dried over sodium sulphate and evaporated to dryness. 54.67 g of product is obtained that is purified eluting with a hexane/ethyl acetate mixture (4-1). 36.83 g of product is thus obtained.
18 g of product prepared in the previous stage are hydrogenated in solution in 360 ml of tetrahydrofurane in the presence of 0.240 g of palladium on carbon followed by filtering. The catalyst is washed with a little tetrahydrofurane. 100 ml of solvent is evaporated and a solution is obtained which is used as it is in the following stage.
A solution containing 15.31 g of product from the previous stage in 250 ml of tetrahydrofurane is cooled down under argon to 0xc2x0 C. 31 ml of tetrabutylammonium fluoride (1M in THF) is added dropwise. The reaction medium is diluted with 400 ml of a hexane/ethyl acetate mixture (1-2). 300 ml of a solution of 10% of sodium hydrogen sulphate is added followed by decanting, drying and evaporating to dryness. The crude product obtained is solubilized in 20 ml of ethyl ether. The reaction medium is cooled down to xe2x88x9210xc2x0 C. and 80 ml of pentane is added under agitation. The suspension obtained is agitated at xe2x88x9220xc2x0 C., followed by filtering at xe2x88x9216xc2x0 C. The product obtained is washed with the pentane and dried. 9.4 g of sought product is obtained.
55 g of hydroxy-8-methyl-7-(tetrahydro-2H-pyrane-2-yl)-2H-1-benzopyrane-2-one is added to 250 ml of anhydrous dimethylformamide heated to 40xc2x0 C., and a solution of 58.3 g of diphenyldiazomethane in 250 ml of dimethyl formamide is added dropwise. The addition is carried out over 3 hours whilst maintaining the temperature at 40xc2x0 C.
Several portions of 3 g of diphenyldiazomethane are added again and agitation is carried out for one hour at 40xc2x0 C.
The reaction medium is poured into 2 l of sulphuric ether. The organic solution is washed with an aqueous solution of sodium bicarbonate, with solution of soda (0.1 M), with water and salt water followed by evaporation to dryness. The residue is agitated in an isopropyl ether-hexane mixture (1-2). The insoluble part is separated and dried. 20.5 g of sought product is obtained.
CCM CH2Cl2xe2x80x94AcOEt (95-5). Rf=0.44.
35 ml of a 0.9 M solution of hydrochloric acid in methanol are added to a solution containing a mixture of 20 g of the product of stage A, 100 ml of dichloromethane and 100 ml of methanol. Agitation is carried out for 2 hours at ambient temperature and the solvents are evaporated. The residue is taken up in absolute ethanol cooled down to 0xc2x0 C. The insoluble part is separated and rinsed with ice cold alcohol then with sulphuric ether followed by drying. 15.53 g of product is recovered which is taken up in ether, separated and dried. 14.54 g of sought product is obtained. NMR 1H (300 MHz, CDCl3, ppm)
2.31 (s, 3H), 5.62 (s, 1H), 6.35 (s, 1H), 6.78 (d, 1H, J=_Hz), 7.75 (d, 1H, J=_Hz), 6.99 to 7.10 (m, _H), 7.30 to 7.42 (m, _H).
A mixture of 91.13 g of the product of stage B, 58.6 g of 6-deoxy-5-C-methyl-4-O-methyl-L-lyxo-hexopyranose and 80 g of triphenylphoshine in 900 ml of dichloromethane are cooled down to 0xc2x0 C. 60 ml of diisopropylazodicarboxylate is added dropwise. Agitation is carried out for 1 hour at ambient temperature.
34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate are added. Agitation is carried out for 1 hour at ambient temperature. 34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate are added and agitation is carried out for 12 hours at ambient temperature. Concentration is carried out under reduced pressure. Chromatograph is carried eluting with a toluene/isopropyl alcohol mixture (95-5). After combining the fractions and evaporation of the solvents, 86.83 g of sought product is recovered after recrystallization from isopropyl ether. NMR 1H (300 MHz, CDCl3, ppm)
1.13 (s, 3H), 1.37 (s, 3H), 2.24 (s, 3H), 2.69 (s, 1H), 2.79 (s, 1H), 3.38 (d, 1H, J=10 Hz), 3.60 (s, 3H), 4.24 (m, 1H), 4.28 (m, 1H), 5.56 (s, 1H), 5.64 (d, 1H, J=1.5 Hz), 6.35 (s, 1H), 7.18 (d, 1H), 7.81 (d, 1H), 7.39 (m, 10 H).
26.6 g of imidazole and 70.15 ml of diisopropylethylamine are added to a solution cooled down to 0xc2x0 C., containing 80 g of the product of the previous stage and 600 ml of dichloromethane. 33.5 ml of triethylsilyl chloride is added dropwise. Agitation is carried out for 1 hour at ambient temperature followed by washing with an aqueous solution of sodium dihydrogen phosphate (1M), with water and with salt water, drying over magnesium sulphate, filtering and concentration. 97.58 g of product is recovered which is purified by chromatography on silica eluting with the dichloromethane acetone mixture (0.8 to 1%). 46.5 g of product is obtained. NMR 1H (300 MHz, CDCl3-d6, ppm)
0.60 (q, _H, J=_Hz), 0.74 (q, _H, J=_Hz), 0.97 (t, _H, J=_Hz), 1.00 (t, _H, J=_Hz), 1.10 (s, 3H), 1.32 (s, 3H), 2.24 (s, 2H), 2.74 (s, 1H), 3.31 (d, 1H, J=_Hz), 3.54 (s, 3H), 4.07 (m, 1H), 4.29 (dd, 1H, J=_Hz), 5.50 (s, 1H), 5.64 (d, 1H, J=_Hz, 6.35 (s, 1H), 7.28 (d, 1H, J=_Hz), 7.81 (d, 1H, J=_Hz), 7.40 (m).
19 ml of dihydropyrane and 400 mg of paratoluene sulphonic acid (PTSA) are added to a solution containing 67 g of the product of the previous stage and 1 l of dichloromethane. Agitation is carried out for 40 minutes at ambient temperature, 300 mg of PTSA is added. After 30 minutes, 100 mg of PTSA is added, then another 100 mg of PTSA. Agitation is carried out for 20 more minutes, then finely ground sodium hydrogen carbonate is introduced. Agitation is carried out for 10 minutes, the reaction medium is diluted with a hexane/ethyl acetate mixture (1-2), washed with water and with salt water followed by drying, filtering and evaporating the solvents. The product obtained is chromatographed eluting with a heptane/ethyl acetate mixture (4-1). 77.9 g of sought product is recovered. NMR 1H (300 MHz, DMSO-d6, ppm)
0.64 (q, _H, J=_Hz), 0.73 (q, _H, J=_Hz), 0.95 to 1.32 (_H), 2.25 (s, _H), 2.27 (s, _H), 3.30 (d, _H, J=_Hz), 3.4 (d, _H, J=_Hz), 3.50 (m, 2H, 3.93 (m, 2H), 3.53 (s, _H), 3.54 (s, _H), 4.04 to 4.15, 4.36 (dd, _H), J=_Hz), 4.94 (l), 4.96 (l), 5.50 (sl, _H), 5.65 (bs), 6.37 (s, 1H), 7.15 (d, _H, J=_Hz), 7.19 (d, _H, J=_Hz), 7.81 (m, 1H), 7.30 to 7.44, 1.47 to 2.00.
15 g of the product of the previous stage is hydrogenated in 150 ml of absolute ethanol in the presence of palladium on carbon (2 g, 10%). The catalyst is eliminated by filtration and the solvents are evaporated to dryness. 14.4 g of produce is obtained.
6.52 g of dimethylaminopyridine are added to a solution containing 14.37 g of the product of the previous stage and 150 ml of dichloromethane. 2.72 ml of acetic anhydride is introduced dropwise. Agitation is carried out at ambient temperature under argon for 1 hour followed by diluting with 200 ml of dichloromethane, washing with an aqueous solution of sodium dihydrogen phosphate, drying over magnesium sulphate, filtering and concentrating. 14.9 g of sought product is obtained.
27 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofurane is introduced dropwise at 0xc2x0 C. to a solution containing 15.2 ml of product of the previous stage in 250 m of THF. Agitation is carried out under argon for 48 hours at ambient temperature. The medium is diluted with an ethyl acetate/hexane mixture, washed with water and with salt water followed by drying, filtering and concentrating to dryness. 13 g of a product is obtained which is triturated in pentane, the supernatant is eliminated and the operation is repeated several times. The product is maintained at +4xc2x0 C., ground in the presence of pentane, the insoluble part is filtered, rinsed and dried. 6.99 g of sought product is obtained. NMR 1H (300 MHz, CDCl3-d6, ppm)
1.09 (s, 3H), 1.11 (s, 3H), 1.35 (s, 3H), 1.36 (s, 1H), 1.50 to 1.90 (m, 8), 2.23 (s, 3H), 2.24 (s, 3H), 2.76 (s, 3H), 3.28 (d, 1H, J=_Hz), 3.33 (d, 1H, J=_Hz), 3.63 (s, 3H), 3.64 (s, 3H), 3.54 (m), 3.97 (m), 4.07 (m), 4.20 to 4.30 (xe2x80x94, 2H), 4.59 (m, _H), 4.82 (m, _H), 5.63 (bs, _H), 5.85 (bs, _H), 7.20 (d, 1H, J=_Hz), 7.88 (m, _H).